Specific Clinical Features Described for Rare Variant of Stiff-Person Syndrome

Neurology Today
4 December 2008; Volume 8(23); p 16

GOODMAN, ALICE

Investigators describe distinctive features to a rare variant of Stiff-person syndrome.

The stiff-person syndrome (SPS) is characterized by progressive muscle stiffness in axial and proximal limb muscles, accompanied by antibodies to glutamic acid decarboxylase (GAD) or amphiphysin antibodies. But SPS with amphiphysin Ab - which occurs in 10 percent of cases - has eluded clinical description.

Now, a new retrospective study reported online ahead of the Dec. 9 print edition of Neurology identifies distinctive clinical features of SPS with amphiphysin Ab.

We demonstrate that SPS with amphiphysin Ab is a cancer-associated syndrome, while SPS with elevated GAD Ab is not, the study author Beth B. Murinson, MD, assistant professor of neurology at Johns Hopkins School of Medicine in Baltimore, told Neurology Today. She co-authored the study with Joseph B. Guarnaccia, MD, director of the Multiple Sclerosis Treatment Center at Griffin Hospital in Derby, CT.

The investigators reviewed the medical records of 116 SPS patients with GAD Ab and 11 with amphiphysin Ab. They observed distinct clinical patterns in patients with amphiphysin-associated SPS: they were all women, older (mean age was 60), and were more likely to have stiffness in the arms and neck. Ten of 11 had breast cancer; one developed the cancer five years after symptom-onset. Among those with the more common GAD Ab-associated variant, 70 percent were female, the mean age at onset was 44, and only 37 percent had symptoms in the arms and neck.

While diabetes mellitus occurs frequently in patients with GAD Ab SPS, it was not found in any of the patients with amphiphysin Ab SPS. Diabetes monitoring is essential for comprehensive care of patients with GAD Ab-associated SPS, Dr. Murinson said.

Figure. DR. BETH B. MURINSON: We demonstrate that SPS with amphiphysin Ab is a cancer- associated syndrome, while SPS with elevated GAD Ab is not.

[ Click here to enlarge ]

She noted that amphiphysin Abs are expressed with other antineoplastic antibodies, and are associated with other neurologic disorders, including sensory neuronopathy, encephalopathy, and myelopathy.

But, she said, a finding of amphiphysin Ab in patients with profound stiffness mandates a search for breast cancer and secondarily, lung cancer, she said.

The SPS variants respond to different treatments, Dr. Murinson said. GAD Ab-associated SPS usually responds to IVIg, while amphiphysin Ab-associated SPS appears to respond to steroids, plasmapheresis, and treatment of a cancer if one is found.

It is not clear why the two variants of SPS are different clinically. Laboratory testing for GAD Ab is widely available, Dr. Murinson noted, but amphiphysin Ab are measured in few laboratories. Thus, amphiphysin Ab-associated SPS should be specifically suspected and testing sought out, she said.

In an accompanying editorial, Amelia Evoli, MD, of the neurosciences department at Catholic University in Rome, Italy, agreed that a prompt search for amphiphysin Abs and a thorough workup for breast cancer should be undertaken in a woman with SPS who does not have GAD Abs.

A GAD Ab-negative patient may be dismissed as seronegative, risking overlooking a malignant tumor whose treatment could improve neurologic symptoms, she said. She cautioned that the associated malignancy is not always breast cancer.

Some neurologists have a misconception that SPS is the most common finding in patents seropositive for amphiphysin Ab, said Sean J. Pittock, MD, associate professor of neurology and a specialist in autoimmune neurological disorders at the Mayo Clinic in Rochester, MN.

But, he said, according to a report he and coauthors at Mayo published in the 2005 Annals of Neurology about 71 patients with amphiphysin Ab, most patients with amphiphysin Ab do not have SPS. Only 10 percent of women and 4 percent of men fulfill diagnostic criteria for SPS, although about 39 percent of women and 12 percent of men exhibit SPS in addition to other multifocal neurological manifestations. Dr. Pittock was not involved with the current study.

Dr. Pittock disagreed with the paper's conclusion that individual testing for amphiphysin Ab alone should be sought in patients who have SPS but are GAD Ab-negative that could be paraneoplastic. A patient suspected of having a paraneoplastic disease warrants a comprehensive paraneoplastic antibody evaluation - not just a test for amphiphysin Ab, he said.

In the 2005 study, the investigators found that 74 percent of patients with amphiphysin Ab have other coexisting neural autoantibodies, he continued. Targeting multiple autoantigens may contribute to the multifocal neurological manifestations often encountered in individual patients with paraneoplastic disorders. Furthermore, the profile of antibodies detected helps direct the search for the appropriate cancer, Dr. Pittock said.

For example, the presence of amphiphysin Ab in women implicates either breast (around 60 percent) or small cell (around 40 percent usually lung) cancers. For a woman with amphiphysin Ab, the coexistence of neuronal nuclear or other cytoplasmic autoantibodies - such as ANNA-1 [anti-hu], CRMP5-IgG, PCA-2 - would direct the clinician toward a small cell lung cancer rather than a breast cancer, he explained.

He complimented the authors for describing the different patterns of distribution of stiffness in patients with GAD Ab-associated SPS and amphiphysin Ab-associated SPS. A pattern of stiffness that is more generalized and predominantly involves the limbs and neck should prompt the clinician to test for neural antibody markers of cancer, especially in patients with GAD Ab-negative SPS, he said. Repetitive.

Dr. Murinson added, however, because amphiphysin Ab-associated SPS is a rare variant, future clinical studies may have to await the development of an infrastructure supporting multicenter research in this area.

• Evoli A. Editorial: Antibody-phenotype correlation in stiff-person syndrome.

• Murinson BB, Guarnaccia JB. Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease.

• Pittock SJ, Lucchinetti CF, Lennon VA, et al. Amphiphysin autoimmunity: paraneoplastic accompaniments.